Occupational lung diseases are caused by harmful dust, particles, mists, vapors, or gases inhaled while a person works. The type of lung disease that may develop often depends on where in the airways or lungs an inhaled substance ends up. Many particles can be trapped in the nose or large airways but smaller particles, gases, mists or vapors may reach the lungs. In the lungs, particles may dissolve and may be absorbed into the bloodstream. The solid particles that don""t dissolve are generally removed by the body""s defenses.
Fortunately, the body has several means to rid inhaled undesired particles. The airways provide mucus that coats particles so they can be coughed up more easily. In particular, the lungs have special scavenger cells that engulf most particles that render the particles harmless to the individual.
The type of particles often produces different reactions in the body. Particles such as plant pollen can cause allergic reactions such as hay fever or asthma. Particles such as coal dust, carbon, and tin oxide don""t produce much of a reaction in the lungs but can end up causing serious life threatening results such as black lung disease caused by coal dust. Other particles, such as quartz dust and asbestos, may cause permanent scarring of lung tissue (pulmonary fibrosis). In large enough quantities, certain particles, such as asbestos, can cause cancer in smokers. Lung diseases caused by dusts are called xe2x80x9cpneumoconiosisxe2x80x9d.
Of particular concern is a type of pneumoconiosis, referred to as xe2x80x9cberylliosisxe2x80x9d, and is associated with beryllium. Beryllium is a silver-grey metallic element that occurs in at least 30 minerals and can be found in coal, oil, soil and volcanic dust. Because of its light weight, stiffness, high melting point and high heat capacity, beryllium has been used in various materials such as windshield frames and other structures in high-speed aircraft and space vehicles, aircraft and space shuttle brakes, satellite mirrors and space telescopes, inertial guidance systems and gyroscopes, neutron moderator or reflector in nuclear reactors, X-ray windows and nuclear weapons components.
Beryllium fumes and dust are classified among the most toxic substances currently known. The World Health Organization""s International Agency for Research on Cancer, and Agencies of the U.S. Department of Health and Human Service, such as the National Institute for Environmental Health Sciences, and the National Institute for Occupational Safety and Health, have classified beryllium as a possible cause of cancer in humans. The Environmental Protection Agency, by Act of Congress, lists beryllium as a toxic air pollutant that needs to be controlled in our communities. Communities have become contaminated with beryllium from factories, mines or by uncontrolled burning of fossil fuels.
There are two forms of berylliosis: acute and chronic. Acute berylliosis is characterized by a sudden, rapid onset of severe inflammation of the lungs (pneumonitis), coughing, increasing breathlessness (dyspnea), and other associated symptoms. For some individuals, the skin or the eyes may be affected. The more common and chronic form of the disease develops slowly and, in some cases, may not become apparent for many years after initial beryllium exposure. Chronic berylliosis disease (CBD) is characterized by the abnormal formation of inflammatory masses or nodules (granulomas) within certain tissues and organs and widespread scarring and thickening of deep lung tissues (interstitial pulmonary fibrosis). The development of granulomas affects primarily the lungs, however, it may also occur within other bodily tissues and organs, such as the skin and underlying (subcutaneous) tissues or the liver. Individuals with chronic berylliosis are often afflicted with dry coughing, fatigue, weight loss, chest pain, and increasing shortness of breath.
When loss of lung function is detected, treatment may involve taking various corticosteroids, generally referred to as xe2x80x9csteroidsxe2x80x9d, medicines that reduce inflammation. One of the most common corticosteroids prescribed for CBD is prednisone. If successful, treatment with prednisone can slow the progress of CBD by reducing the buildup of scar tissue and delaying permanent lung damage. Unfortunately, many individuals do not respond well to steroid treatment. Many individuals cannot tolerate the side effects of long-term steroid treatment, such as slow healing of infections, calcium loss from the bones, higher blood cholesterol, and fluid and salt retention which can cause or aggravate a heart or kidney disease. Individuals who cannot take steroids may continue to lose lung function. As a result they are likely to experience a poorer quality of life, possibly becoming an invalid, and their life span maybe shortened. A need therefore exists, for compositions and methods to prevent lung disease associated with airborne particulates/contaminants that are directed toward the disease process, such that such diseases are physiologically prevented, reversed or inhibited.
Dusts found in work place environments can affect the body in various ways. Some are not dangerous, others can cause injury and even death. Once inhaled, the components of the dust invade the lungs. Lung diseases caused by dusts are referred to as xe2x80x9cpneumoconiosisxe2x80x9d and are named by the dust that produces the pneumoconiosis, e.g., beryllium is berylliosis, silica or quartz is silicosis. Surprisingly, it has been discovered that porphyrin analogues, as described below, can remove or prevent build up of these toxic substances in a subject""s lung or body tissue(s). Not to be limited by theory, it is considered that the porphyrin analogues have a binding cavity sufficient in diameter with attractive forces (lone pair pi cloud interactions) formed by heteroatoms that complex or chelate with the beryllium metal ion(s). It has been found that non-harmful metal ions already bound by the porphyrin analogue can be displaced by amore toxic metal ion. By porphyrin complexation with these harmful metal ions, the toxic effects of physical contact with these foreign materials can be minimized by the removal of the toxic metals from the tissue(s) by the porphyrin analogues of the present invention.
In one aspect, the present invention provides methods to treat or prevent pneumoconiosis, i.e., berylliosis, in a subject by administering to the subject a therapeutically effective amount of a porphyrin analogue or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, such that pneumoconiosis in the subject is treated or prevented. A preferred method of administration of the porphyrin analogue or pharmaceutically acceptable salt, ester, amide, or prodrug thereof is in the form of an aerosol. It is considered that administration by use of an inhaler provides a suitable means to bring into contact the porphyrin analogue with the lung tissue most likely affected by the toxic metal(s). Suitable porphyrin analogues include, for example, hemin, meso-tetra (4-carboxyphenyl) porphyrin, phthalocyanine tetrasulfonate, meso-tetra (4-sulfonatophenyl) porphyrin, and magnesium phthalocyanine tetrasulfonate tetra soldium salt porphyrin. In particular, meso-tetra (4-carboxyphenyl) porphyrin and meso-tetra-(4-sulfonate phenyl) have been tested in the lungs of mice and have been found to be non-toxic.
The present invention further provides packaged pharmaceutical compositions for treating or preventing pneumoconiosis in a subject, such as berylliosis. The packaged pharmaceutical compositions include, a container that holds a therapeutically effective amount of at least one porphyrin analogue and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof and instructions for use of the porphyrin analogue for the treatment or prevention of pneumoconiosis in the subject.
The present invention also provides pharmaceutical compositions that include a therapeutically effective amount of at least one porphyrin analogue sufficient to treat or prevent pneumoconiosis, i.e., berylliosis in a subject along with a pharmaceutically acceptable carrier. Preferably the pharmaceutical composition in the carrier can be used in the form of an aerosol for inhalation therapy.